The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4, and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various disease states are also discussed in the book by Rokach.
Recently a number of compounds of formula (1) in which A represents optionally substituted heterocycle, and pharmaceutically acceptable salts thereof, have been disclosed as leukotriene antagonists and inhibitors of leukotriene biosynthesis. ##STR3##
EP 480,717 discloses compounds of formula (1) in which A represents optionally substituted quinoline; more specifically disclosed is the compound in which A represents 7-chloro-2-quinolinyl. U.S. Pat. 5,270,324 discloses two compounds of formula (1) in which A represents 6-fluoro- or 6,7-difluoro-2-quinolinyl. In co-pending application U.S. Ser. No. 994,869, filed Dec. 22, 1992 (EP Published Application 604,114) there is disclosed compounds in which A is halo-substituted thieno[2,3-b]pyridine, particularly 2,3-dichlorothieno[2,3-b]pyridin-5-yl.
The reported syntheses of compounds of formula (1) proceed through their corresponding methyl esters and involve coupling methyl 1-(mercaptomethyl)cyclopropaneacetate with a mesylate exemplified by formula (III), generated in situ. The methyl esters of compounds of formula (I) are hydrolyzed to the free acids and the latter converted directly to the corresponding sodium salts. This process is not particularly suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediates and/or the final products, and the product yields are low. Furthermore, the final products, as the sodium salts, were obtained as amorphous solids which are often not ideal for pharmaceutical formulation.
Accordingly, there exists the need for an efficient synthesis of compounds of formula (1) which is amenable to scale-up, provides improved overall product yield, and provides the product sodium salts in crystalline form.
King et al, J. Org. Chem., 1993, 58:3731-3735 reported the synthesis of L-699,392 via the following sequence: ##STR4##